Hypophosphatasia (HPP), a heritable metabolic bone disease, is caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, and therefore features low serum levels of alkaline phosphatase. HPP manifests clinically due to impaired mineralization of skeletal matrix (causing rickets or osteomalacia) because the excess levels of pyrophosphate, the substrate for TNSALP, inhibits the mineralization process. Recently, a task force was established by the American Society for Bone and Mineral Research to investigate the association of atypical subtrochanteric and diaphyseal femoral fractures (ASFFs) with the long-term use of bisphosphonates for osteoporosis. Because these fractures resemble pseudofractures seen in adult hypophosphatasia, and that bisphosphonates are chemical derivatives of pyrophosphate, one of their recommendations was to sequence the TNSALP gene in these osteoporosis patients to see if they are carriers of TNSALP mutations or polymorphisms that may predispose them to these unusual and debilitating fractures. We have now documented such a case. A 55 year-old woman, after treatment for four years with oral and later intravenous bisphosphonates for presumed osteoporosis, suffered simultaneous atraumatic bilateral ASFFs. After sequencing her TNSALP gene, we identified a single mutation (c.212 G>A, p.Arg71His). This defect can be inherited as a single dominant mild mutation or combined with a second mutation in severe recessive HPP. The patient had never been diagnosed with HPP, although her serum ALP was low (26 U/L, Nl 32 - 116 U/L). We hypothesize that being either a carrier of a recessive TNSALP mutation or having a mild dominant form (diagnosed or undiagnosed) of HPP due to a single TNSALP mutation predisposes osteoporosis patients to ASFFs. Treatment with bisphosphonates then further exacerbates skeletal disease leading to overt fracture. We hypothesize that a significant number of osteoporosis patients using bisphosphonates and having ASFFs will carry TNSALP mutations. Therefore, we will test whether osteoporosis patients who are using bisphosphonate therapy and experience ASFFs have a higher frequency of TNSALP mutations or polymorphisms than control groups. If our hypothesis is validated, osteoporosis patients should be screened for serum TNSALP activity, and then further tested for TNSALP substrate levels and perhaps TNSALP mutations. Those with evidence of carrier status or dominant HPP should not be treated with bisphosphonates. This will reduce the incidence of ASFFs in osteoporosis patients.